【药物名称】Epibatidine, CMI-477(enantiomer), CMI-545(racemate (exo)-isomer), CMI-488
化学结构式(Chemical Structure):
参考文献No.239314
标题:Total synthesis of epibatidine
作者:Broka, C.A.
来源:Tetrahedron Lett 1993,34(20),3251-4
合成路线图解说明:

The key to the total synthesis of epibatidine is to construct the 7-azabicyclo[2.2.1]heptane system. A number of papers about the syntheses of racemic epibatidine and both of its enantiomers have been published. The different methodologies for the construction of this novel ring system can be classified into four categories. 1) Intramolecular nucleophilic ring closure of 1-amino-4-substituted-cyclohexane derivatives. Broka reported the first total synthesis of (?-epibatidine in 1993. The preparation of ketoaldehyde (III) was achieved as a single isomer by reaction of enal (II) with 2-(trimethylsilyloxy)-1,3-butadiene. (III) was converted into aminomesylate (IV) in 15 steps, which was heated in CHCl3 to give the mesylate salt of (I) in excellent yield. Starting from 6-chloronicotinaldehyde, epibatidine was obtained via a reaction sequence of 17 steps in an overall yield of 6%. Broka's work confirmed the correctness of the structure proposed by Daly et al.

参考文献No.258338
标题:Total synthesis and determination of the absolute configuration of epibatidine
作者:Fletcher, S.R.; Baker, R.; Chambers, M.S.; Herbert, R.H.; Hobbs, S.C.; Thomas, S.R.; Verrier, H.M.; Watt, A.P.; Ball, R.G.
来源:J Org Chem 1994,59(7),1771-8
合成路线图解说明:

2) Fletcher and his group also utilized an intramolecular displacement to construct the azabicycloheptane ring system. 4-Benzylamino-1,2-epoxycyclohexane (V) was cyclized in N-methyl-pyrrolidone upon heating to yield the exo-alcohol (VI), which was further converted into ketone (VIII). Introduction of the pyridyl group, dehydration and catalytic hydrogenation resulted primarily in the endo-isomer (Xa), which could be epimerized using t-BuOK to afford the more stable exo-isomer (Xb). Fletcher et al. also succeeded in separating the enantiomers of (VII) as their Mosher ester and in establishing the absolute configuration of (I) as (1R,2R,4S).

参考文献No.265998
标题:A practical route to epibatidine
作者:Sz醤tay, C.; Kardos-Balogh, Z.; Moldvai, I.; Sz醤tay, C. Jr.; Major-Temesv醨y, E.; Blask? G.
来源:Tetrahedron Lett 1994,35(19),3171-4
合成路线图解说明:

4) Szantay et al. reported a practical route to epibatidine by using commonly available starting materials under convenient reaction conditions. The alpha,beta-unsaturated ketone (XV) was synthesized by Wittig reaction of 6-chloronicotinaldehyde and the appropriate phosphorane. Ring closure took place by treatment of compound (XV) with KF/Al2O3. Reduction of the keto group followed by mesylation and subsequent reduction of the nitro group afforded amine (XVII). Upon boiling in toluene, (XVII) was immediately transformed into the undesired endo-isomer of epibatidine (XVIII). Taking advantage of Fletcher's endo- to exo-epimerization, (XVIII) was converted into racemic epibatidine in moderate yield. The advantage of this route is that no protection and consequently no deprotection steps are involved. But the combined yield in the last two steps is only 30%.

参考文献No.269234
标题:Total synthesis of a frog poison, (?-epibatidine, a potent non-opioid analgesic
作者:Okabe, K.; Natsume, M.
来源:Chem Pharm Bull 1994,42(7),1432-6
合成路线图解说明:

15) Natsume's approach to epibatidine was to construct the basic skeleton of (I) by condensation of N-protected 7-azabicyclo[2.2.1]heptan-2-one with 5-lithio-2-chloropyridine, which was similar to Fletcher's synthesis. However, the azabicycloheptanone (LX) was derived from the Diels-Alder adduct (LIX) of 1-(p-toluenesulfonyl)pyrrole and dimethyl acetylenedicarboxylate through a standard sequence of reactions. Reaction of (LX) with 5-lithio-2-methoxypyridine gave (LXI), which was dehydrated to (LXII) with Burgess reagent. Catalytic hydrogenation of (LXII) over palladium-on-charcoal in 2-propanol/water (12:1) containing 1% HCl afforded (LXIII) and (LXIV) in 22% and 72% yields, respectively. Treatment of (LXIV) with POCl3/DMF obtained (LXV) in 70% yield.

参考文献No.382953
标题:A short and efficient total synthesis of (?-epibatidine
作者:Zhang, C.; Trudell, M.L..
来源:J Org Chem 1996,61(20),7189-91
合成路线图解说明:

16) A similar approach was described by Zhang and Trudell in a recent report: The known 7-azabicyclo[2.2.1]heptan-2-one (VIII) was conveniently synthesized by the [4+2] cycloaddition of methyl 3-bromopropynoate (LXVII) and N-BOC-pyrrole (LXVI). They modified Fletcher's synthesis rendering it more stereoselective and suitable for the preparation of (I) on a large scale. The tertiary alcohol (IX) was successfully deoxygenated by a radical reaction via its methyl oxalyl ester with Bu3SnH in the presence of AIBN. This afforded the deoxygenated product stereoselectively as the endo-isomer (Xa).

参考文献No.414548
标题:Enantioselective approach to 7-azabicyclo[2.2.1]heptane ring systems using D-(-)-quinic acid as the chiral educt: Application to the formal synthesis of (+)-epibatidine
作者:Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G.P.; Zanirato, V.
来源:Tetrahedron Lett 1997,38(4),681-4
合成路线图解说明:

10) Albertini et al. reported a formal synthesis of epibatidine utilizing the enantiopure cyclohexanone (XXXVIII) as a convenient starting material which was easily available from D-(-)quinic acid (XXXVII). An important step in this synthesis was the regioselective intramolecular nucleophilic ring opening of the vicinal diol cyclic sulfate (XXXIX). When (XXXIX) was subjected to hydrogenation, the azido group was converted into an amino group and an internal displacement took place spontaneously to form the inner salt (XL). Three standard manipulations furnished the optically pure ketone (VIII), which had already been converted to epibatidine as described by Fletcher and coworkers.

参考文献No.432496
标题:Epibatidine
作者:Bai, D.; Xu, R.; Zhu, X.
来源:Drugs Fut 1997,22(11),1210
合成路线图解说明:

The key to the total synthesis of epibatidine is to construct the 7-azabicyclo[2.2.1]heptane system. A number of papers about the syntheses of racemic epibatidine and both of its enantiomers have been published. The different methodologies for the construction of this novel ring system can be classified into four categories. 1) Intramolecular nucleophilic ring closure of 1-amino-4-substituted-cyclohexane derivatives. Broka reported the first total synthesis of (?-epibatidine in 1993. The preparation of ketoaldehyde (III) was achieved as a single isomer by reaction of enal (II) with 2-(trimethylsilyloxy)-1,3-butadiene. (III) was converted into aminomesylate (IV) in 15 steps, which was heated in CHCl3 to give the mesylate salt of (I) in excellent yield. Starting from 6-chloronicotinaldehyde, epibatidine was obtained via a reaction sequence of 17 steps in an overall yield of 6%. Broka's work confirmed the correctness of the structure proposed by Daly et al.

合成路线图解说明:

2) Fletcher and his group also utilized an intramolecular displacement to construct the azabicycloheptane ring system. 4-Benzylamino-1,2-epoxycyclohexane (V) was cyclized in N-methyl-pyrrolidone upon heating to yield the exo-alcohol (VI), which was further converted into ketone (VIII). Introduction of the pyridyl group, dehydration and catalytic hydrogenation resulted primarily in the endo-isomer (Xa), which could be epimerized using t-BuOK to afford the more stable exo-isomer (Xb). Fletcher et al. also succeeded in separating the enantiomers of (VII) as their Mosher ester and in establishing the absolute configuration of (I) as (1R,2R,4S).

合成路线图解说明:

3) Corey's group published a stereocontrolled route to both enantiomers of epibatidine through HPLC separation of N-(trifluoroacetyl)epibatidine using chiral columns. A Diels-Alder reaction between (Z)-alpha,beta-unsaturated ester (XI) and 1,3-butadiene furnished the cis-4,5-disubstituted cyclohexene (XII), which was converted to the vicinal dibromide (XIII). Upon treatment with t-BuOK, (XIII) underwent intramolecular nucleophilic substitution to give compound (XIV) with the azabicyclo[2.2.1]heptane ring system.

合成路线图解说明:

4) Szantay et al. reported a practical route to epibatidine by using commonly available starting materials under convenient reaction conditions. The alpha,beta-unsaturated ketone (XV) was synthesized by Wittig reaction of 6-chloronicotinaldehyde and the appropriate phosphorane. Ring closure took place by treatment of compound (XV) with KF/Al2O3. Reduction of the keto group followed by mesylation and subsequent reduction of the nitro group afforded amine (XVII). Upon boiling in toluene, (XVII) was immediately transformed into the undesired endo-isomer of epibatidine (XVIII). Taking advantage of Fletcher's endo- to exo-epimerization, (XVIII) was converted into racemic epibatidine in moderate yield. The advantage of this route is that no protection and consequently no deprotection steps are involved. But the combined yield in the last two steps is only 30%.

合成路线图解说明:

5) Later on, Szantay's group modified the above described procedure based on a polarity reversal approach (8). Compound (XVI) was thus converted to the ring closure precursor (XIX) in 7 steps. Base-catalyzed ring closure of (XIX) afforded racemic epibatidine.

合成路线图解说明:

6) Nakai et al. used 3-lithio pyridine as a nucleophile to attack ketone (XX), yielding the tertiary alcohol (XXI) stereoselectively. Reductive elimination of the hydroxyl group followed by oxidation and acid hydrolysis gave N-oxide (XXII), which was treated with POCl3 to produce (I) and (XXIII) in low yields.

合成路线图解说明:

7) Sestanj and his coworkers succeeded in synthesizing epibatidine by a conjugate addition intramolecular displacement strategy. Conjugate addition of higher order cyanocuprate (XXIV) to alpha,beta-unsaturated ketone (XXV) obtained the ketone (XXVI), which was converted to (XXVII) in 60% overall yield. Under Mitsunobu conditions with DEAD and PPh3 as reagents, only the beta-amino-tosylate cyclized to give the epibatidine ring system.

合成路线图解说明:

8) Ko and his coworkers employed the [4+2] addition reaction of 1-(2-chloro-5-pyridyl)cyclohexa-2,4-diene (XXIX) with singlet oxygen to form the bicyclic peroxide (XXX) as the key step. (XXX) was converted to azidomesylate (XXXI) in 42% overall yield. Based on Broka's epibatidine synthesis, (?-(I) was obtained through reduction and intramolecular displacement.

合成路线图解说明:

9) The first asymmetric synthesis of (-)-epibatidine was disclosed by Trost and Cook through a Pd-catalyzed desymmetrization of cis-dibenzoyloxy-2-cyclohexene (XXXII) and a Pd-catalyzed cross-coupling reaction. Dibenzoate (XXXII) was reacted with trimethylsilylazide in the presence of a Pd catalyst with chiral phosphine ligands to give ent-(XXXIII) in excellent yield and e.e. (XXXIII) was converted to vinyl bromide (XXXIV), which was coupled with the stable organostannane (XXXV) through a Pd(0)-catalyzed reaction to give enone (XXXVI). Reduction of the double bond and carbonyl, O-mesylation of the resulting amido alcohol and finally heating of the crude amino mesylate in acetonitrile produced (-)-epibatidine.

合成路线图解说明:

10) Albertini et al. reported a formal synthesis of epibatidine utilizing the enantiopure cyclohexanone (XXXVIII) as a convenient starting material which was easily available from D-(-)quinic acid (XXXVII). An important step in this synthesis was the regioselective intramolecular nucleophilic ring opening of the vicinal diol cyclic sulfate (XXXIX). When (XXXIX) was subjected to hydrogenation, the azido group was converted into an amino group and an internal displacement took place spontaneously to form the inner salt (XL). Three standard manipulations furnished the optically pure ketone (VIII), which had already been converted to epibatidine as described by Fletcher and coworkers.

合成路线图解说明:

11) Hassner and Belostotskii reported a simple synthesis of 7-alkyl-7-azabicyclo[2.2.1]heptanes. The starting aminoalcohols which were easily available from the monoethylene ketal of 1,4-cyclohexanedione (XLI) were treated with triphenylphosphine-carbon tetrachloride, leading to 7-alkyl-7-azabicyclo[2.2.1]heptanes (XLIII) in good yields. Recently, Davis et al. described the microbial hydroxylations of (XLIII) using the fungi Beauveria bassiana, Rhizopus nigricans, Aspergillus ochraceus and Rhizopus arrhizus as the primary organisms. Though the enantioselectivity was not high enough, these results demonstrated the potential of microbiological oxygenations to deliver enantioselective reactions.

合成路线图解说明:

12) Reaction of N-substituted-pyrrole derivatives with activated dienophiles. Retrosynthetic analysis revealed that the [4+2] cycloaddition reaction between pyrrole and dienophiles should be a general method for the synthesis of the 7-azanorborane ring system. Unfortunately, pyrrole is not a good diene for the Diels-Alder reactions. Pyrrole and its derivatives readily undergo Michael addition upon treatment with dienophiles, and the resulting 7-aza[2.2.1]bicycloheptenes are thermodynamically unstable. In order to stablize the resultant products and accelerate the cycloaddition reaction, N-protected pyrroles with a decreased aromaticity of the pyrrole ring are usually used as diene components and acetylene equivalents are used as dienophiles. In 1993 Shen et al. first reported a 4-step synthesis of racemic epibatidine. A Diels-Alder reaction of N-carbomethoxypyrrole (XLV) and phenylsulfonyl(6-chloro-3-pyridyl)acetylene (XLVI) afforded the adduct (XLVII) in 70% yield. Desulfonation and concomitant reduction of conjugated double bond with sodium amalgam resulted in a mixture of 1:2 ratio of exo-(XLVIII) to endo-(XLVIII).

合成路线图解说明:

13) Later on Carroll and Kotian modified Shen's route by replacement of N-carbomethoxypyrrole with N-(t-carbobutoxy)pyrrole in order to avoid the drastic reaction condition in the deprotection step. However, there was the problem of competing retro Diels-Alder reaction of the cycloadduct (L) and dechlorination. Therefore, the selective reduction of the least substituted double bond of (L) was carried out first. Desulfonation and simultaneous reduction of (LI) with amalgam obtained a 1:2 mixture of exo-(LII) and endo-(LII) analogous to Shen's report. The endo-isomer was epimerized to the exo-isomer in 46% yield using Fletcher's procedure. Finally, deprotection of the BOC group under mild conditions produced (I) in nearly quantitative yield.

合成路线图解说明:

14) It is noteworthy that Regan et al. described a very concise synthesis of racemic epibatidine. The key step was a reductive Pd-catalyzed Heck-type coupling of the known starting materials olefin (LVI) and 2-chloro-5-iodopyridine (LVII). The desired exo-isomer (LVIII) was formed stereoselectively.

合成路线图解说明:

15) Natsume's approach to epibatidine was to construct the basic skeleton of (I) by condensation of N-protected 7-azabicyclo[2.2.1]heptan-2-one with 5-lithio-2-chloropyridine, which was similar to Fletcher's synthesis. However, the azabicycloheptanone (LX) was derived from the Diels-Alder adduct (LIX) of 1-(p-toluenesulfonyl)pyrrole and dimethyl acetylenedicarboxylate through a standard sequence of reactions. Reaction of (LX) with 5-lithio-2-methoxypyridine gave (LXI), which was dehydrated to (LXII) with Burgess reagent. Catalytic hydrogenation of (LXII) over palladium-on-charcoal in 2-propanol/water (12:1) containing 1% HCl afforded (LXIII) and (LXIV) in 22% and 72% yields, respectively. Treatment of (LXIV) with POCl3/DMF obtained (LXV) in 70% yield.

合成路线图解说明:

16) A similar approach was described by Zhang and Trudell in a recent report: The known 7-azabicyclo[2.2.1]heptan-2-one (VIII) was conveniently synthesized by the [4+2] cycloaddition of methyl 3-bromopropynoate (LXVII) and N-BOC-pyrrole (LXVI). They modified Fletcher's synthesis rendering it more stereoselective and suitable for the preparation of (I) on a large scale. The tertiary alcohol (IX) was successfully deoxygenated by a radical reaction via its methyl oxalyl ester with Bu3SnH in the presence of AIBN. This afforded the deoxygenated product stereoselectively as the endo-isomer (Xa).

合成路线图解说明:

17) Pandey et al. reported an efficient synthesis of epibatidine via [3+2] cycloaddition of nonstabilized azomethine ylide and substituted 6-chloro-3-vinylpyridine. The precursor (LXX) was obtained in 73% yield from N-BOC pyrrolidine (LXIX) by standard manipulations. The [3+2] cycloaddition between (LXX) and alpha,beta-unsaturated ester (LXXI) furnished cycloadduct (LXXII) stereoselectively. Decarboxylation followed by reductive N-debenzylation converted (LXXII) into (I) in 78% overall yield.

合成路线图解说明:

18) Ring contraction of the tropinone skeleton via a Favorskii rearrangement. Bai et al. utilized the readily available tropinone (LXXIII) as a starting material. Compound (LXXIV), which could be obtained from (LXXIII) in one step, was brominated with cupric bromide to give the monobromide (LXXV). Without separation of the two isomers, both isomers (LXXV) underwent Favorskii rearrangement to yield the expected ester (LXXVI). The key intermediate (LXXVII) was then obtained by selenation of (LXXVI) followed by selenoxide elimination. A palladium-catalyzed Heck-type coupling of (LXXVII) and 2-chloro-5-iodopyridine (LVII) furnished the exo-isomer (LXXVIII) stereoselectively in 56% yield. Conversion of (LXXVIII) to (I) was achieved by radical decarboxylation of the corresponding thiohydroxamic ester followed by cleavage of the carbamate with iodotrimethyl silane.

合成路线图解说明:

19) Intramolecular cyclization of substituted proline derivatives. Rapoport et al. developed an asymmetric methodology which had potential for the enantiospecific synthesis of (+)- and (-)-epibatidine. The triflate (LXXIX) was readily synthesized from levulinic acid in 3 straightforward steps. Alkylation of S-thiolactam (LXXX) prepared from L-glutamic acid with triflate (LXXIX), followed by sulfide contraction provided the carbamate (LXXXI). (LXXXI) was then converted into keto acid (LXXXII). (LXXXII) was decarboxylated and the resulting iminium ions were subjected to intramolecular cyclization to give a mixture of trans-2,3-disubstituted-7-azabicyclo[2.2.1]heptanes (LXXXIII) and (LXXXIV). This mixture was selectively converted into (+)- and (-)-N-BOC-7-azabicyclo[2.2.1]heptane-2-ones (VIII), which are versatile intermediates for the enantiospecific synthesis of (+)- and (-)-epibatidine.

参考文献No.450363
标题:Epibatidine. Its pharmacological actions and utility for studying neuronal nicotinic receptors
作者:Kellar, K.J.
来源:Neurotransmissions 1995,111-5
合成路线图解说明:

The key to the total synthesis of epibatidine is to construct the 7-azabicyclo[2.2.1]heptane system. A number of papers about the syntheses of racemic epibatidine and both of its enantiomers have been published. The different methodologies for the construction of this novel ring system can be classified into four categories. 1) Intramolecular nucleophilic ring closure of 1-amino-4-substituted-cyclohexane derivatives. Broka reported the first total synthesis of (?-epibatidine in 1993. The preparation of ketoaldehyde (III) was achieved as a single isomer by reaction of enal (II) with 2-(trimethylsilyloxy)-1,3-butadiene. (III) was converted into aminomesylate (IV) in 15 steps, which was heated in CHCl3 to give the mesylate salt of (I) in excellent yield. Starting from 6-chloronicotinaldehyde, epibatidine was obtained via a reaction sequence of 17 steps in an overall yield of 6%. Broka's work confirmed the correctness of the structure proposed by Daly et al.

参考文献No.450364
标题:Chemistry of 7-azabicyclo[2.2.1]hepta-2,5-dienes, 7-azabicyclo[2.2.1]hept-2-enes, and 7-azabicyclo[2.2.1]hepatanes
作者:Chen, Z.; Trudell, M.L.
来源:Chem Rev 1996,961179-93
合成路线图解说明:

12) Reaction of N-substituted-pyrrole derivatives with activated dienophiles. Retrosynthetic analysis revealed that the [4+2] cycloaddition reaction between pyrrole and dienophiles should be a general method for the synthesis of the 7-azanorborane ring system. Unfortunately, pyrrole is not a good diene for the Diels-Alder reactions. Pyrrole and its derivatives readily undergo Michael addition upon treatment with dienophiles, and the resulting 7-aza[2.2.1]bicycloheptenes are thermodynamically unstable. In order to stablize the resultant products and accelerate the cycloaddition reaction, N-protected pyrroles with a decreased aromaticity of the pyrrole ring are usually used as diene components and acetylene equivalents are used as dienophiles. In 1993 Shen et al. first reported a 4-step synthesis of racemic epibatidine. A Diels-Alder reaction of N-carbomethoxypyrrole (XLV) and phenylsulfonyl(6-chloro-3-pyridyl)acetylene (XLVI) afforded the adduct (XLVII) in 70% yield. Desulfonation and concomitant reduction of conjugated double bond with sodium amalgam resulted in a mixture of 1:2 ratio of exo-(XLVIII) to endo-(XLVIII).

参考文献No.450370
标题:A practical enantioselective synthesis of epibatidine
作者:Sz醤tay, C.; Kardos-Balogh, Z.; Moldvai, I.; Sz醤tay, C. Jr.; Major-Temesv醨y, E.; Blask? G.
来源:Tetrahedron 1996,5211053-62
合成路线图解说明:

5) Later on, Szantay's group modified the above described procedure based on a polarity reversal approach (8). Compound (XVI) was thus converted to the ring closure precursor (XIX) in 7 steps. Base-catalyzed ring closure of (XIX) afforded racemic epibatidine.

参考文献No.450373
标题:Synthesis and biological evaluation of (?-epibatidine and the congeners
作者:Senokuchi, K.; Nakai, H.; Kawamura, M.; et al.
来源:Synlett 1994,343-4
合成路线图解说明:

6) Nakai et al. used 3-lithio pyridine as a nucleophile to attack ketone (XX), yielding the tertiary alcohol (XXI) stereoselectively. Reductive elimination of the hydroxyl group followed by oxidation and acid hydrolysis gave N-oxide (XXII), which was treated with POCl3 to produce (I) and (XXIII) in low yields.

参考文献No.450374
标题:Synthesis of epibatidine
作者:Sestanj, K.; Melenski, E.; Jirkovsky, I.
来源:Tetrahedron Lett 1994,355417-20
合成路线图解说明:

7) Sestanj and his coworkers succeeded in synthesizing epibatidine by a conjugate addition intramolecular displacement strategy. Conjugate addition of higher order cyanocuprate (XXIV) to alpha,beta-unsaturated ketone (XXV) obtained the ketone (XXVI), which was converted to (XXVII) in 60% overall yield. Under Mitsunobu conditions with DEAD and PPh3 as reagents, only the beta-amino-tosylate cyclized to give the epibatidine ring system.

参考文献No.450375
标题:The total synthesis of epibatidine
作者:Ko, S.Y.; Lerpiniere, J.; Linney, I.D.; Wrigglesworth, R.
来源:J Chem Soc Ser Chem Commun 1994,1775-6
合成路线图解说明:

8) Ko and his coworkers employed the [4+2] addition reaction of 1-(2-chloro-5-pyridyl)cyclohexa-2,4-diene (XXIX) with singlet oxygen to form the bicyclic peroxide (XXX) as the key step. (XXX) was converted to azidomesylate (XXXI) in 42% overall yield. Based on Broka's epibatidine synthesis, (?-(I) was obtained through reduction and intramolecular displacement.

参考文献No.450376
标题:An asymmetric synthesis of (-)-epibatidine
作者:Trost, B.M.; Cook, G.R.
来源:Tetrahedron Lett 1996,377485-8
合成路线图解说明:

9) The first asymmetric synthesis of (-)-epibatidine was disclosed by Trost and Cook through a Pd-catalyzed desymmetrization of cis-dibenzoyloxy-2-cyclohexene (XXXII) and a Pd-catalyzed cross-coupling reaction. Dibenzoate (XXXII) was reacted with trimethylsilylazide in the presence of a Pd catalyst with chiral phosphine ligands to give ent-(XXXIII) in excellent yield and e.e. (XXXIII) was converted to vinyl bromide (XXXIV), which was coupled with the stable organostannane (XXXV) through a Pd(0)-catalyzed reaction to give enone (XXXVI). Reduction of the double bond and carbonyl, O-mesylation of the resulting amido alcohol and finally heating of the crude amino mesylate in acetonitrile produced (-)-epibatidine.

参考文献No.450381
标题:A total synthesis of (?-epibatidine
作者:Clayton, S.C.; Regan, A.C.
来源:Tetrahedron Lett 1993,347493-6
合成路线图解说明:

14) It is noteworthy that Regan et al. described a very concise synthesis of racemic epibatidine. The key step was a reductive Pd-catalyzed Heck-type coupling of the known starting materials olefin (LVI) and 2-chloro-5-iodopyridine (LVII). The desired exo-isomer (LVIII) was formed stereoselectively.

参考文献No.450382
标题:An expeditious synthesis of epibatidine and analogues
作者:Pandey, G.; Bagul, T.D.; Lakshmaiah, G.
来源:Tetrahedron Lett 1994,357439-42
合成路线图解说明:

17) Pandey et al. reported an efficient synthesis of epibatidine via [3+2] cycloaddition of nonstabilized azomethine ylide and substituted 6-chloro-3-vinylpyridine. The precursor (LXX) was obtained in 73% yield from N-BOC pyrrolidine (LXIX) by standard manipulations. The [3+2] cycloaddition between (LXX) and alpha,beta-unsaturated ester (LXXI) furnished cycloadduct (LXXII) stereoselectively. Decarboxylation followed by reductive N-debenzylation converted (LXXII) into (I) in 78% overall yield.

参考文献No.450383
标题:Total synthesis of (?-epibatidine
作者:Xu, R.; Chu, G.; Bai, D.
来源:Tetrahedron Lett 1996,371463-6
合成路线图解说明:

18) Ring contraction of the tropinone skeleton via a Favorskii rearrangement. Bai et al. utilized the readily available tropinone (LXXIII) as a starting material. Compound (LXXIV), which could be obtained from (LXXIII) in one step, was brominated with cupric bromide to give the monobromide (LXXV). Without separation of the two isomers, both isomers (LXXV) underwent Favorskii rearrangement to yield the expected ester (LXXVI). The key intermediate (LXXVII) was then obtained by selenation of (LXXVI) followed by selenoxide elimination. A palladium-catalyzed Heck-type coupling of (LXXVII) and 2-chloro-5-iodopyridine (LVII) furnished the exo-isomer (LXXVIII) stereoselectively in 56% yield. Conversion of (LXXVIII) to (I) was achieved by radical decarboxylation of the corresponding thiohydroxamic ester followed by cleavage of the carbamate with iodotrimethyl silane.

参考文献No.450384
标题:Synthesis of (?-epibatidine and its analogues
作者:Bai, D.; Xu, R.; Chu, G.; Zhu, X.
来源:J Org Chem 1996,614600-6
合成路线图解说明:

18) Ring contraction of the tropinone skeleton via a Favorskii rearrangement. Bai et al. utilized the readily available tropinone (LXXIII) as a starting material. Compound (LXXIV), which could be obtained from (LXXIII) in one step, was brominated with cupric bromide to give the monobromide (LXXV). Without separation of the two isomers, both isomers (LXXV) underwent Favorskii rearrangement to yield the expected ester (LXXVI). The key intermediate (LXXVII) was then obtained by selenation of (LXXVI) followed by selenoxide elimination. A palladium-catalyzed Heck-type coupling of (LXXVII) and 2-chloro-5-iodopyridine (LVII) furnished the exo-isomer (LXXVIII) stereoselectively in 56% yield. Conversion of (LXXVIII) to (I) was achieved by radical decarboxylation of the corresponding thiohydroxamic ester followed by cleavage of the carbamate with iodotrimethyl silane.

参考文献No.450385
标题:Synthesis of (+)- and (-)-N-BOC-7-azabicyclo[2.2.1]heptan-2-ones, versatile intermediates for the enantiospecific synthesis of (+)- and (-)-epibatidine and analogues
作者:Hern醤dez, A.; Marcos, M.; Rapoport, H.
来源:J Org Chem 1995,602638-91
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19) Intramolecular cyclization of substituted proline derivatives. Rapoport et al. developed an asymmetric methodology which had potential for the enantiospecific synthesis of (+)- and (-)-epibatidine. The triflate (LXXIX) was readily synthesized from levulinic acid in 3 straightforward steps. Alkylation of S-thiolactam (LXXX) prepared from L-glutamic acid with triflate (LXXIX), followed by sulfide contraction provided the carbamate (LXXXI). (LXXXI) was then converted into keto acid (LXXXII). (LXXXII) was decarboxylated and the resulting iminium ions were subjected to intramolecular cyclization to give a mixture of trans-2,3-disubstituted-7-azabicyclo[2.2.1]heptanes (LXXXIII) and (LXXXIV). This mixture was selectively converted into (+)- and (-)-N-BOC-7-azabicyclo[2.2.1]heptane-2-ones (VIII), which are versatile intermediates for the enantiospecific synthesis of (+)- and (-)-epibatidine.

参考文献No.468895
标题:New synthesis of 7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-2-ene. A key intermediate in the synthesis of epibatidine and analogs
作者:Abraham, P.; Brieaddy, L.E.; Carroll, F.I.; Lee, J.R.; Liang, F.
来源:Tetrahedron Lett 1998,39(30),5321
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21) A new synthesis of epibatidine has been reported: The reaction of 2-tosyl-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylic acid tert-butyl ester (I) with tributyltin hydride (II) by means of azobis(isobutyronitrile) (AIBN) in benzene gives the tin derivative (III), which by treatment with tetrabutylammonium fluoride in THF provides 7-azabicyclo[2.2.1]hept-2-ene-7-carboxylic acid tert-butyl ester (IV). The condensation of (IV) with 5-iodopyridine-2-amine (V) by means of palladium acetate/tetrabutylammonium chloride/potassium formate in hot DMF yields exo-2-(6-amino-3-pyridyl)-7-azabicyclo[2.2.1]heptane-7-carbo-xylic acid tert-butyl ester (VI), which is finally submitted to diazotization with NaNO2/HCl and treated with CuCl.

参考文献No.482937
标题:The total synthesis of the analgesic alkaloid epibatidine
作者:Giblin, G.M.P.; Jones, C.D.; Simpkins, N.S.
来源:J Chem Soc - Perkins Trans I 1998,(22),3689
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20) A total synthesis of epibatidine has been reported: The cyclization of 1-(tert-butoxycarbonyl)pyrrole (I) with tosylacetylene (II) by means of H2 over Pd/C in acetonitrile gives the bicyclic compound (III), which is condensed with 5-bromo-2-methoxypyridine (IV) by means of BuLi in THF yielding the 2exo-(6-methoxy-3-pyridyl) derivative (V). The detosylation of (V) by means of Na(Hg) in methanol/THF affords intermediate (VI), which is treated with POCl3 in DMF to effect the conversion of the methoxypyridine into the desired chloropyridine derivative (VII), with simultaneous elimination of the tert-butoxycarbonyl protecting group and N-formylation. Finally, this formyl group is eliminated with HCl in hot THF.

参考文献No.558748
标题:Total synthesis of (?-epibatidine using a biocatalytic approach
作者:Olivo, H.F.; Hemenway, M.S.
来源:J Org Chem 1999,64(24),8968
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A new total synthesis of racemic epibatidine has been reported: The benzoylation of trans-4-aminocyclohexanol (I) with benzoyl chloride gives the benzamide (II), which is treated with methanesulfonyl chloride and triethylamine to yield the mesylate (III). Cyclization of (III) by means of potassium tert-butoxide in DMF/benzene affords the 7-azanorbornane (IV), which by microbial hydroxylation using the fungus Beauveria bassiana gives stereoselectively the endo-2-hydroxy-7-azanorbornane (V). Oxidation of (V) with TPAP and NMO in dichloromethane yields the ketone (VI), which is condensed with 2-chloro-5-iodopyridine (VII) by means of butyllithium in THF affording exclusively the endo-alcohol (VIII). Reaction of (VIII) with methoxalyl chloride (IX) and DMAP/2,6-lutidine in dichloromethane gives the mixed oxalate (IX), which is reduced with tributyltin hydride and AIBN to yield exclusively the endo-isomer (XI). Isomerization of (XI) by means of potassium tert-butoxide in refluxing tert-butanol affords the exo-isomer (XII), which is finally debenzoylated by treatment with 6N HCl at 100 C.

参考文献No.583050
标题:A formal asymmetric synthesis of (-)-epibatidine using a highly diastereoselective hetero Diels-Alder reaction
作者:Berrien, J.F.; Cabanal Duvillard, I.; Ghosez, L.; Husson, H.P.; Royer, J.
来源:Tetrahedron 2000,56(23),3763
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The synthesis of (-)-7-tosyl-7-azabicyclo[2.2.1]heptan-2-one, a key chiral intermediate for the asymmetric synthesis of (-)-epibatidine has been described: The reaction of (+)-camphorsultam (I) first with triphosgene and DIEA, and then with NH2OH gives the (+)-hydroxamic acid (II), which is oxidized with tetraethylammonium periodate in CH2Cl2 to yield the acylnitroso compound (III). The asymmetric hetero Diels-Alder cycloaddition of (III) with 2-(tert-butyldimethylsilyloxy)-1,3-cyclohexadiene (IV) affords the (1S,4R)-cycloadduct (V), which is cleaved with Mo(CO)6 providing the (+)-6-amino-2-cyclohexenone (VI) as s single diastereomer. Reduction of the carbonyl group of (VI) with NaBH4 and CeCl3 in methanol gives a 9:1 mixture of cis:trans-diastereomers, from which the major (+)-cis-diastereomer (VII) is isolated by chromatography. Elimination of the chiral auxiliary with KOH in MeOH gives the chiral (-)-oxazolidinone (VIII), which is tosylated with TsCl and NaH in THF yielding the (-)-N-tosyloxazolidinone (IX). Bromination of (IX) with Br2 in DME affords a 80:20 mixture of diastereomeric bromohydrins, from which the desired (-)-diastereo-mer (X) is isolated by column chromatography. Reductive debromination of (X) with Bu3SnH and AIBN in hot toluene followed by hydrolysis of the oxazolidinone ring by treatment with LiOH in MeOH, yields the (+)-aminocyclohexanediol (XI). The cyclization of (XI) by means of PPh3 and diethyl azodicarboxylate (DEAD) in THF affords the chiral (-)-7-azabicyclo[2.2.1]heptanol (XII) which is finally oxidized with oxalyl chloride and TEA in DMSO to provide the target chiral intermediate (-)-7-tosyl-7-azabicyclo[2.2.1]heptan-2-one.

参考文献No.605721
标题:Microbiological oxygenation of bridgehead azabicycloalkanes
作者:Davis, C.R.; Johnson, R.A.; Cialdella, J.I.; Liggett, W.F.; Mizsak, S.A.; Marshall, V.P.
来源:J Org Chem 1997,62(7),2244-51
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11) Hassner and Belostotskii reported a simple synthesis of 7-alkyl-7-azabicyclo[2.2.1]heptanes. The starting aminoalcohols which were easily available from the monoethylene ketal of 1,4-cyclohexanedione (XLI) were treated with triphenylphosphine-carbon tetrachloride, leading to 7-alkyl-7-azabicyclo[2.2.1]heptanes (XLIII) in good yields. Recently, Davis et al. described the microbial hydroxylations of (XLIII) using the fungi Beauveria bassiana, Rhizopus nigricans, Aspergillus ochraceus and Rhizopus arrhizus as the primary organisms. Though the enantioselectivity was not high enough, these results demonstrated the potential of microbiological oxygenations to deliver enantioselective reactions.

参考文献No.801064
标题:The synthesis of (+)- and (-)-epibatidine
作者:Fletcher, S.R.; Baker, R.; Chambers, M.S.; Hobbs, S.C.; Mitchell, P.J.
来源:J Chem Soc Ser Chem Commun 1993,1216-8
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2) Fletcher and his group also utilized an intramolecular displacement to construct the azabicycloheptane ring system. 4-Benzylamino-1,2-epoxycyclohexane (V) was cyclized in N-methyl-pyrrolidone upon heating to yield the exo-alcohol (VI), which was further converted into ketone (VIII). Introduction of the pyridyl group, dehydration and catalytic hydrogenation resulted primarily in the endo-isomer (Xa), which could be epimerized using t-BuOK to afford the more stable exo-isomer (Xb). Fletcher et al. also succeeded in separating the enantiomers of (VII) as their Mosher ester and in establishing the absolute configuration of (I) as (1R,2R,4S).

合成路线图解说明:

4) Szantay et al. reported a practical route to epibatidine by using commonly available starting materials under convenient reaction conditions. The alpha,beta-unsaturated ketone (XV) was synthesized by Wittig reaction of 6-chloronicotinaldehyde and the appropriate phosphorane. Ring closure took place by treatment of compound (XV) with KF/Al2O3. Reduction of the keto group followed by mesylation and subsequent reduction of the nitro group afforded amine (XVII). Upon boiling in toluene, (XVII) was immediately transformed into the undesired endo-isomer of epibatidine (XVIII). Taking advantage of Fletcher's endo- to exo-epimerization, (XVIII) was converted into racemic epibatidine in moderate yield. The advantage of this route is that no protection and consequently no deprotection steps are involved. But the combined yield in the last two steps is only 30%.

参考文献No.801066
标题:Stereocontrolled total synthesis of (+)- and (-)-epibatidine
作者:Corey, E.J.; Loh, T.E.; Achyutha-Rao, S.; Daley, D.C.; Sarshar, S.
来源:J Org Chem 1993,585600-2
合成路线图解说明:

3) Corey's group published a stereocontrolled route to both enantiomers of epibatidine through HPLC separation of N-(trifluoroacetyl)epibatidine using chiral columns. A Diels-Alder reaction between (Z)-alpha,beta-unsaturated ester (XI) and 1,3-butadiene furnished the cis-4,5-disubstituted cyclohexene (XII), which was converted to the vicinal dibromide (XIII). Upon treatment with t-BuOK, (XIII) underwent intramolecular nucleophilic substitution to give compound (XIV) with the azabicyclo[2.2.1]heptane ring system.

参考文献No.801075
标题:A simple method of preparation of 7-alkyl-7-azabicyclo[2.2.1]heptanes
作者:Hassner, A.; Belostotskii, A.M.
来源:Tetrahedron Lett 1995,361709-12
合成路线图解说明:

11) Hassner and Belostotskii reported a simple synthesis of 7-alkyl-7-azabicyclo[2.2.1]heptanes. The starting aminoalcohols which were easily available from the monoethylene ketal of 1,4-cyclohexanedione (XLI) were treated with triphenylphosphine-carbon tetrachloride, leading to 7-alkyl-7-azabicyclo[2.2.1]heptanes (XLIII) in good yields. Recently, Davis et al. described the microbial hydroxylations of (XLIII) using the fungi Beauveria bassiana, Rhizopus nigricans, Aspergillus ochraceus and Rhizopus arrhizus as the primary organisms. Though the enantioselectivity was not high enough, these results demonstrated the potential of microbiological oxygenations to deliver enantioselective reactions.

参考文献No.801078
标题:Synthesis of (+) and (-) epibatidine
作者:Kotian, P.L.; Carrol, F.I.
来源:Synth Commun 1995,2563-71
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13) Later on Carroll and Kotian modified Shen's route by replacement of N-carbomethoxypyrrole with N-(t-carbobutoxy)pyrrole in order to avoid the drastic reaction condition in the deprotection step. However, there was the problem of competing retro Diels-Alder reaction of the cycloadduct (L) and dechlorination. Therefore, the selective reduction of the least substituted double bond of (L) was carried out first. Desulfonation and simultaneous reduction of (LI) with amalgam obtained a 1:2 mixture of exo-(LII) and endo-(LII) analogous to Shen's report. The endo-isomer was epimerized to the exo-isomer in 46% yield using Fletcher's procedure. Finally, deprotection of the BOC group under mild conditions produced (I) in nearly quantitative yield.

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